The hormone analog 1-deamino-8-D-arginine vasopressin (1-.beta.-mercaptopropionic acid, 8-D-arginine)-vasopressin or desmopressin, hereinafter also abbreviated as "DDAVP", is an important antidiuretic for treatment of diurea, such as associated with diabetes insipidus, nocturnal enuresis, and urine incontinence.
While differing from native neurohypophyseal vasopressin by exchange of the terminal cysteine moiety by 1-.beta.-mercaptopropionic acid, and replacement of arginine with D-arginine, 1-deamino-8-D-arginine vasopressin will, in the present specification, nevertheless be termed a "nonapeptide derivative." Similarly, synthetic starting materials and intermediates will be termed n-peptide derivatives, where n equals the total number of amino acid and pseudo-amino acid moieties in the respective peptide.
The synthesis of DDAVP by homogeneous phase (U.S. Pat. No. 3,497,491 to Zaoral et al.) and by solid phase (Krchnak, V. and Zaoral M., 1979, Coll. Czechoslov. Chem. Commun. 44:1173-1178) methods has been described. However, 1-deamino-8-D-arginine vasopressin is only obtained in amorphous form with currently known methodology and is, thus, difficult to purify. For therapeutic application, impurities such as those with pressor activity cause complications.
It is known in the art that yield can be increased at the sacrifice of purity, and vice versa, and that the larger the product molecule, the harder and more expensive it is to purify. The medical field demands high purity as a premium, thus, the prevailing emphasis has been on purity. However, currently known methods require excessive purification steps with the inevitable reduction in yield. Purification is costly in terms of manpower hours and the obvious loss of profits from reduced product yield.
Thus, there is a need in the art for synthetic routes for producing DDAVP, wherein the yield achieved in the final steps of synthesis is increased. This will reduce the need for extensive purification of intermediates and product, and provide a superior product in improved yield. There is also a need in the art for an improved method for DDAVP production which is relatively less complex and wherein impurities with pressor effect or other unwanted biological effects will be formed to a lessor extent or more easily eliminated in purification steps.